EP0288758B1 - Dihydropyridinamide, Verfahren zu ihrer Herstellung und ihre Verwendung in Arzneimitteln - Google Patents

Dihydropyridinamide, Verfahren zu ihrer Herstellung und ihre Verwendung in Arzneimitteln Download PDF

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Publication number
EP0288758B1
EP0288758B1 EP88104951A EP88104951A EP0288758B1 EP 0288758 B1 EP0288758 B1 EP 0288758B1 EP 88104951 A EP88104951 A EP 88104951A EP 88104951 A EP88104951 A EP 88104951A EP 0288758 B1 EP0288758 B1 EP 0288758B1
Authority
EP
European Patent Office
Prior art keywords
carboxylic acid
general formula
phenyl
carbon atoms
pyridine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP88104951A
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German (de)
English (en)
French (fr)
Other versions
EP0288758A2 (de
EP0288758A3 (en
Inventor
Jürgen Dipl.-Ing. Stoltefuss
Eckhard Dr. Schwenner
Martin Dr. Bechem
Claudia Dr. Hirth
Michael Dr. Kayser
Matthias Dr. Schramm
Johannes-Peter Dr. Stasch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer AG filed Critical Bayer AG
Priority to AT88104951T priority Critical patent/ATE66209T1/de
Publication of EP0288758A2 publication Critical patent/EP0288758A2/de
Publication of EP0288758A3 publication Critical patent/EP0288758A3/de
Application granted granted Critical
Publication of EP0288758B1 publication Critical patent/EP0288758B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/82—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to dihydropyridinamides, processes for their preparation and their use in medicaments, in particular as medicaments which influence the circulation.
  • 1,4-dihydro-2,6-dimethyl-4-phenyl-pyridine-3,5-dicarboxylic acid diethyl ester is obtained by reacting ethyl benzylidene-acetoacetate with ethyl ⁇ -aminocrotonate or ethyl acetoacetate and ammonia (E. Knoevenagel, Ber. Dtsch. Chem. Ges. 31, 743 (1898)).
  • the compounds according to the invention exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
  • the invention relates to both the antipodes and the racemic forms as well as the diastereomer mixtures.
  • the racemic forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner (cf. E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).
  • Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids.
  • Salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluene sulfonic acid, are preferred or naphthalidine sulfonic acid.
  • reactive acid derivatives are: activated esters, hydroxysuccinimide esters, acid imidazolides, acid halides, mixed anhydrides or the reaction in the presence of cyclohexyl carbodiimide.
  • Water or all inert organic solvents which do not change under the reaction conditions are suitable as solvents. These preferably include alcohols such as methanol, ethanol, Propanol, isopropanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether, or amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, or glacial acetic acid, dimethyl sulfoxide, acetonitrile or pyridine.
  • alcohols such as methanol, ethanol, Propanol, isopropanol
  • ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether
  • amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, or glacial acetic acid, dimethyl sulfoxide
  • reaction temperatures can be varied within a wide range. Generally one works between + 10 ° C and + 150 ° C, preferably between +20 ° C and + 100 ° C. In particular at the boiling point of the respective solvent.
  • the reaction can be carried out at normal pressure, but also at elevated or reduced pressure. Generally one works at normal pressure.
  • the ratio of the substances involved in the reaction is arbitrary. In general, however, one works with molar amounts of the reactants.
  • the substances according to the invention are preferably isolated and purified in such a way that the solvent is distilled off in vacuo and, if appropriate, only after ice cooling. crystalline residue obtained recrystallized from a suitable solvent. In some cases it may be necessary to purify the compounds of the invention by chromatography.
  • aldehydes of the general formula (II) used as starting materials are known or can be prepared by known methods [DOS 21 65 260; 24 01 665; T.D. Harris, G.P. Roth, J. Org. Chem. 44, 2004 (1979); W.J. Dale, H.E. Hennis, J. Am. Chem. Soc. 78: 2543 (1956); Chem., Abstr. 59, 13929 (1963)].
  • ⁇ -ketocarboxylic acid esters of the general formula (III) used as starting materials are known or can be prepared by known methods [D. Borrmann in Houben Weyl's "Methods of Organic Chemistry” Vol. VII / 4, 230 (1968); Y. Oikawa, K. Sugano, O. Yonemitsu, J. Org. Chem. 43, 2087 (1978)].
  • ⁇ -ketocarboxamides of the general formula (IV) used as starting materials are known or can be prepared by known methods [DOS 11 42 859].
  • the enaminocarboxamides of the general formula (V) used as starting materials are known or can be prepared by known methods [DOS 2 228 377].
  • the enaminocarboxylic acid esters of the general formula (VI) used as starting materials are known or can be prepared by known methods [F.A. Glickman, A.C. Cope, J. Am. Chem. Soc. 67, 1017 (1945)].
  • the ylidene- ⁇ -ketocarboxamides of the general formula (VII) used as starting materials and the ylidene- ⁇ -ketocarboxylic acid esters of the general formula (VIII) used as starting materials are known or can be prepared by known methods [G. Jones “The Knoevenagel Condensation” in Organic Reactions Vol. XV, 204 (1967)].
  • process variant H is based on the methodology known from the literature for converting carboxylic acids into carboxamides.
  • the carboxylic acid is first converted into an activated form such as converting the acid chloride or the imidazolide, which are either isolated as such and reacted in a second reaction step, or which are amidated directly to the compounds of the invention in situ.
  • an activated form such as converting the acid chloride or the imidazolide, which are either isolated as such and reacted in a second reaction step, or which are amidated directly to the compounds of the invention in situ.
  • carbodiimides such as cyclohexylcarbodiimide may be used as activating reagents.
  • solvents for process variant H are suitable as solvents for process variant H.
  • solvents for process variant H preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether, or halogenated hydrocarbons such as dichloromethane, trichloromethane or tetrachloromethane, or amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric acid triamide, or hydrocarbons or xenylol, toluene, toluene, toluene, toluene, toluene, toluene, toluene, toluene, toluene, toluene, toluene, toluene, toluene, toluene, toluene, toluene, toluene, toluene, tolu
  • reaction temperatures can be varied within a wide range. Generally one works in a range from -70 ° C to +140 C, preferably from -20 ° C to +100 C.
  • the reaction can be carried out at normal pressure, but also at elevated or reduced pressure. Generally one works at normal pressure.
  • the ratio of the substances involved in the reaction is arbitrary. In general, however, one works with molar amounts of the reactants. However, it has proven advantageous to use the amine in a 5- to 10-fold molar excess. The amine is particularly advantageously used in a large excess as a solvent.
  • the dihydropyridine monocarboxylic acids of the general formula (IX) used as starting materials are known or can be prepared by known methods [DOS 2,847,236; 3,206,671; 2,962,241].
  • amines of the general formula (X) used as starting materials are known or can be prepared by known methods [Houben Weyl's "Methods of Organic Chemistry” Bd XI / 1; Paulsen, Angewandte Chemie 78, 501-566 (1966)].
  • the compounds according to the invention show an unforeseeable, valuable spectrum of pharmacological activity. They affect the heart's contractile force, smooth muscle tone, and electrolyte and fluid balance.
  • They can also be used to treat cardiac arrhythmias, renal failure, cirrhosis of the liver, ascites, pulmonary edema, cerebral edema, pregnancy edema, glaucoma or diabetes mellitus.
  • the cardiac activity of the compounds according to the invention was found on the isolated, stimulated papillary muscle of the guinea pig heart.
  • the test animals 200 g heavy guinea pigs of both sexes
  • papillary muscles that were as small as possible were then extracted from the right ventricle of the heart and fixed horizontally in an organ bath.
  • One end of the muscle was held by two metal electrodes, which simultaneously stimulated the preparation, while the other end of the muscle was connected to a force transducer by a thread.
  • the papillary muscle was stimulated above the threshold with a frequency of 1 Hz.
  • the organ bath with a volume of approx.
  • the substances according to the invention were dissolved in the Krebs-Henseleit solution in a concentration of 10 ⁇ g / ml, if appropriate with a solubilizer (DMSO up to a concentration of 0.5%).
  • DMSO solubilizer
  • the dihydropyridine carbonamides according to the invention showed, based on the control values, an inhibition of the contractile force of the papillary muscle by more than 10%.
  • the new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.
  • auxiliary substances are: water, non-toxic organic solvents, such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut / sesame oil), alcohols (e.g. ethyl alcohol, glycerol), carriers, e.g. natural stone flours (e.g. kaolins, clays, talc, chalk), synthetic stone flours (e.g. highly disperse silica, silicates), sugar (e.g. cane, milk and dextrose), emulsifiers (e.g. polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, Alkyl sulfonates, aryl sulfonates), detergents (e.g.
  • paraffins e.g. petroleum fractions
  • vegetable oils e.g. peanut / sesame oil
  • alcohols e.g. ethyl alcohol, glycerol
  • carriers e.g. natural stone flours (e.g.
  • lignin e.g. lignin, sulfite lye, methyl cellulose, starch and polyvinylpyrrolidone
  • lubricants e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate.
  • the application is carried out in the usual way, preferably orally or parenterally, in particular perlingually or intravenously.
  • tablets can of course be used in addition to the above Carriers also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate along with various additives such as starch, preferably potato starch, gelatin and the like.
  • Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting.
  • the active ingredients can be mixed with various flavor enhancers or colorants.
  • solutions of the active ingredients can be used using suitable liquid carrier materials.
  • R f values DC aluminum foil Merck, layer thickness 0.2 mm, silica gel 60 F 254; Eluent toluene / ethyl acetate in a volume ratio of 1: 2

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Treatment And Processing Of Natural Fur Or Leather (AREA)
EP88104951A 1987-04-09 1988-03-28 Dihydropyridinamide, Verfahren zu ihrer Herstellung und ihre Verwendung in Arzneimitteln Expired - Lifetime EP0288758B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT88104951T ATE66209T1 (de) 1987-04-09 1988-03-28 Dihydropyridinamide, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19873711991 DE3711991A1 (de) 1987-04-09 1987-04-09 Dihydropyridinamide, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln
DE3711991 1987-04-09

Publications (3)

Publication Number Publication Date
EP0288758A2 EP0288758A2 (de) 1988-11-02
EP0288758A3 EP0288758A3 (en) 1989-03-01
EP0288758B1 true EP0288758B1 (de) 1991-08-14

Family

ID=6325224

Family Applications (1)

Application Number Title Priority Date Filing Date
EP88104951A Expired - Lifetime EP0288758B1 (de) 1987-04-09 1988-03-28 Dihydropyridinamide, Verfahren zu ihrer Herstellung und ihre Verwendung in Arzneimitteln

Country Status (20)

Country Link
EP (1) EP0288758B1 (cs)
JP (1) JPS6419066A (cs)
KR (1) KR880012553A (cs)
CN (1) CN88101927A (cs)
AT (1) ATE66209T1 (cs)
AU (1) AU602970B2 (cs)
CA (1) CA1328869C (cs)
CS (1) CS271486B2 (cs)
DD (1) DD274026A5 (cs)
DE (2) DE3711991A1 (cs)
DK (1) DK192988A (cs)
ES (1) ES2039267T3 (cs)
FI (1) FI881609A7 (cs)
GR (1) GR3002679T3 (cs)
HU (1) HU204786B (cs)
IL (1) IL85992A0 (cs)
NO (1) NO881308L (cs)
NZ (1) NZ224125A (cs)
PT (1) PT87182B (cs)
ZA (1) ZA882449B (cs)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3833892A1 (de) * 1988-10-05 1990-04-12 Bayer Ag Basische 4-aryl-dhp-amide, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln
US5124508A (en) * 1990-08-14 1992-06-23 The Scabbard Corp. Application of sheet batteries as support base for electronic circuits
US5147985A (en) * 1990-08-14 1992-09-15 The Scabbard Corporation Sheet batteries as substrate for electronic circuit
DE4100125A1 (de) * 1991-01-04 1992-07-09 Bayer Ag Neue dihydropyridinamide, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln
GB9100932D0 (en) * 1991-01-16 1991-02-27 Tomlin Trevor V Frames
DE4118707A1 (de) * 1991-06-07 1992-12-10 Bayer Ag Pharmazeutische verwendung von 3-formyl-1,4-dihydropyridinen, neue verbindungen und verfahren zu ihrer herstellung
GB9119983D0 (en) * 1991-09-19 1991-11-06 Erba Carlo Spa Dihydropyridine derivatives useful in antitumor therapy
DE4134760A1 (de) * 1991-10-22 1993-07-08 Bayer Ag Aryl-chinolyl-substituierte 1,4-dihydropyridin-dicarbonsaeurederivate, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln
JP2007230869A (ja) * 2004-04-05 2007-09-13 Takeda Chem Ind Ltd アルドステロン受容体拮抗剤
WO2010015652A2 (en) * 2008-08-07 2010-02-11 Smithkline Beecham Corporation Thiazole compounds as activators of soluble guanylate cyclase
CN103380117A (zh) * 2011-01-21 2013-10-30 Abbvie公司 激酶的吡啶酰胺抑制剂
CN115403519B (zh) * 2022-08-31 2024-03-01 河南师范大学 一种可见光驱动的n-取代异烟酰胺类化合物的合成方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2228377A1 (de) * 1972-06-10 1974-01-03 Bayer Ag Dihydropyridin-carbonsaeureamide, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
FR2508446B1 (fr) * 1981-06-25 1986-05-02 Rhone Poulenc Agrochimie Herbicides a fonctions amide et ester derives de la pyridine ainsi que leur procede de preparation et leur application
EP0111453A1 (de) * 1982-12-10 1984-06-20 Ciba-Geigy Ag Amid-Verbindungen
US4868181A (en) * 1986-08-04 1989-09-19 E. I. Du Pont De Nemours And Company 1,4-dihydropyridine derivatives with calcium agonist and alpha1 -antagonist activity

Also Published As

Publication number Publication date
FI881609A7 (fi) 1988-10-10
PT87182B (pt) 1995-01-31
HU204786B (en) 1992-02-28
DK192988A (da) 1988-10-10
ES2039267T3 (es) 1993-09-16
JPS6419066A (en) 1989-01-23
DK192988D0 (da) 1988-04-08
PT87182A (pt) 1989-05-12
AU1413788A (en) 1988-10-13
ZA882449B (en) 1988-09-29
HUT46664A (en) 1988-11-28
IL85992A0 (en) 1988-09-30
CN88101927A (zh) 1988-11-16
CS271486B2 (en) 1990-10-12
DE3864177D1 (de) 1991-09-19
EP0288758A2 (de) 1988-11-02
CS235488A2 (en) 1990-02-12
CA1328869C (en) 1994-04-26
NO881308L (no) 1988-10-10
EP0288758A3 (en) 1989-03-01
GR3002679T3 (en) 1993-01-25
DE3711991A1 (de) 1988-10-20
NZ224125A (en) 1990-11-27
DD274026A5 (de) 1989-12-06
KR880012553A (ko) 1988-11-28
AU602970B2 (en) 1990-11-01
NO881308D0 (no) 1988-03-24
ATE66209T1 (de) 1991-08-15
FI881609A0 (fi) 1988-04-07

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